JP2020015679A - Compositions for improving lower urinary tract symptoms - Google Patents
Compositions for improving lower urinary tract symptoms Download PDFInfo
- Publication number
- JP2020015679A JP2020015679A JP2018139168A JP2018139168A JP2020015679A JP 2020015679 A JP2020015679 A JP 2020015679A JP 2018139168 A JP2018139168 A JP 2018139168A JP 2018139168 A JP2018139168 A JP 2018139168A JP 2020015679 A JP2020015679 A JP 2020015679A
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- composition
- urinary tract
- symptoms
- polymethoxyflavonoid
- lower urinary
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Abstract
Description
本発明は、畜尿症状、排尿症状、排尿後症状、過活動膀胱などの下部尿路症状改善用組成物に関する。 The present invention relates to a composition for improving lower urinary tract symptoms such as animal urine symptoms, urination symptoms, post-micturition symptoms, and overactive bladder.
健常人の膀胱は、最大で３００〜５００ｍｌの尿を溜めることができる。成人では、膀胱内に約２００ｍｌの尿が溜まると、尿意に関するシグナルが脳に送られ、初発尿意を感じる。かかるシグナルを脳が受け取ると副交感神経が興奮し、その結果、膀胱のムスカリン受容体が刺激され平滑筋（排尿筋）が収縮する。一方、蓄尿段階では、交感神経が優位になり、排尿筋は弛緩した状態にある。 The bladder of a healthy person can store up to 300-500 ml of urine. In an adult, when about 200 ml of urine accumulates in the bladder, a signal relating to urination is sent to the brain, and the person feels first urination. When the brain receives such a signal, the parasympathetic nerve is excited, and as a result, the muscarinic receptor of the bladder is stimulated and the smooth muscle (detrusor) contracts. On the other hand, in the urine storage stage, the sympathetic nerve is dominant, and the detrusor muscle is in a relaxed state.
現代の高齢化かつストレス過剰な社会の進展に伴い、下部尿路症状（Ｌｏｗｅｒ Ｕｒｉｎａｒｙ Ｔｒａｃｔ Ｓｙｍｐｔｏｍ：ＬＵＴＳ）を有する中高年者が増えている。ＬＵＴＳを有する男性患者の受診率は女性よりも高く、医療経済上の負担が大きい。ＬＵＴＳは自覚的な煩わしさやＱＯＬの低下と密接に関係しており、ＬＵＴＳを来す疾患の疾患重症度、治療選択及び治療効果判定における重要な評価項目となっている。一方、ＬＵＴＳの疾患特異性は低く、それだけで原因疾患を診断することは困難である。また、ＬＵＴＳの重症度は必ずしも客観的所見の重症度と相関しない。 2. Description of the Related Art With the progress of a modern aging and overstressed society, middle-aged and elderly people have lower urinary tract symptoms (LUTS). The consultation rate of male patients with LUTS is higher than that of women, and the burden on medical economics is greater. LUTS is closely related to subjective annoyance and QOL reduction, and is an important evaluation item in disease severity, treatment selection, and treatment effect judgment of a disease that causes LUTS. On the other hand, the disease specificity of LUTS is low, and it is difficult to diagnose the causative disease by itself. Also, the severity of LUTS does not always correlate with the severity of objective findings.
ＬＵＴＳは、蓄尿と排尿（尿排出）に関連する症状を網羅する症状である。原因としては下部尿路機能障害（Ｌｏｗｅｒ Ｕｒｉｎａｒｙ Ｔｒａｃｔ Ｄｙｓｆｕｎｃｔｉｏｎ：ＬＵＴＤ）が示唆されるが、膀胱炎、前立腺炎、尿道炎、膀胱癌、膀胱結石などの器質的疾患でも起こり得る。 LUTS are symptoms covering symptoms related to urine storage and urination (urine excretion). As a cause, lower urinary tract dysfunction (LUTD) is suggested, but it can also occur in organic diseases such as cystitis, prostatitis, urethritis, bladder cancer, and bladder stones.
２００２年の国際禁制学会（Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｃｏｎｔｉｎｅｎｃｅ Ｓｏｃｉｅｔｙ：ＩＣＳ）によるＩＣＳ用語基準に基づき、ＬＵＴＳは蓄尿症状、排尿症状及び排尿後症状を含む総称的な症状として用いられている。なお、ＬＵＴＳは、従前の広義の排尿障害に相当する。 Based on the ICS terminology standard of the International Continuity Society (ICS) in 2002, LUTS is used as a generic symptom, including urinary storage symptoms, urinary symptoms and post-micturition symptoms. LUTS corresponds to a conventional urination disorder in a broad sense.
ＬＵＴＳにおいて、生殖器・尿路痛症候群及び下部尿路機能障害を示唆する症状症候群があり、そのうちの一つが過活動膀胱（Ｏｖｅｒａｃｔｉｖｅ Ｂｌａｄｄｅｒ：ＯＡＢ）である。ＯＡＢは、蓄尿段階の膀胱が過剰に反応する結果、突然の強い尿意を感じる症候群であり、通常は昼間頻尿及び夜間頻尿を伴い、加齢とともに有病率が増加することが報告されている。ＯＡＢの患者では、交感神経と副交感神経との調和が崩れ、蓄尿時にも関わらず排尿筋が不随意に収縮することから尿意切迫感や頻尿が起こると考えられている。ただし、他の尿道−膀胱機能障害による場合もある。 In LUTS, there are symptomatic syndromes suggesting genital and urinary tract pain syndromes and lower urinary tract dysfunction, and one of them is overactive bladder (OAB). OAB is a syndrome that suddenly feels strong urination as a result of the bladder in the urinary storage stage being over-reactive, and is usually accompanied by daytime and nocturia, and its prevalence is reported to increase with age. I have. In OAB patients, harmony between the sympathetic nerve and the parasympathetic nerve is disrupted, and the detrusor muscle involuntarily contracts in spite of urinary storage, so urinary urgency and frequent urination are thought to occur. However, it may be due to other urethral-bladder dysfunction.
男性において、ＯＡＢは、前立腺肥大症を伴うことが報告されている。前立腺は、膀胱の直ぐ下で尿道を取り囲むように存在する。前立腺が加齢に伴って肥大化すると、膀胱出口の尿道が圧迫され、尿勢減弱や残尿感を引き起こす。女性のＯＡＢ患者は、加齢や出産などによって骨盤底筋が緩むことが原因で「腹圧性尿失禁」（くしゃみや咳、運動などで一過的に腹部に力が加わる動作の際の尿漏れ）を高頻度で併発することが報告されている。これは、女性の尿道が男性の尿道よりも短いためである。 In men, OAB has been reported to be associated with benign prostatic hyperplasia. The prostate is located just below the bladder and surrounds the urethra. As the prostate enlarges with age, the urethra at the outlet of the bladder is compressed, causing a decrease in urine pressure and a feeling of residual urine. Female OAB patients suffer from "tensive stress incontinence" due to pelvic floor muscle loosening due to aging, childbirth, etc. (Urine leakage during movements that temporarily apply force to the abdomen due to sneezing, coughing, exercise, etc.) ) Has been reported to occur frequently. This is because the female urethra is shorter than the male urethra.
ＬＵＴＳは、膀胱から尿道までを含めた範囲において、様々な要因で発症する加齢性の症状であるといえる。したがって、ＬＵＴＳを予防することは、快適な高齢者生活を送る上で極めて重要である。 LUTS can be said to be an age-related symptom that develops due to various factors in the range from the bladder to the urethra. Therefore, preventing LUTS is extremely important for a comfortable elderly life.
ＬＵＴＳの治療の一つに薬物療法がある。例えば、ＯＡＢの治療にはオキシブチニンやソリフェナシンなどの抗コリン薬、ミラベグロンなどのβ３アドレナリン受容体作動薬が使用され、前立腺肥大症の治療にはタムスロシンなどのα１アドレナリン受容体遮断薬、タダラフィルなどのホスホジエステラーゼ５阻害薬、デュタステリドなどの５α還元酵素阻害薬、クロルマジノンなどの抗アンドロゲン薬などが使用されている。 Drug treatment is one of the treatments for LUTS. For example, anti-cholinergic drugs such as oxybutynin and solifenacin, and β3 adrenergic receptor agonists such as mirabegron are used for the treatment of OAB, α1 adrenergic receptor blockers such as tamsulosin, and phosphodiesterases such as tadalafil for treating prostatic hypertrophy. 5 inhibitors, 5α reductase inhibitors such as dutasteride, antiandrogens such as chlormadinone, and the like have been used.
ＬＵＴＳの治療としては、長期間に及ぶことがあることから、長期間の服用に対して安全性が高い有効成分によることが望まれる。例えば、特許文献１には、ノビレチン、タンゲレチン、３’，４’，５，７−テトラメチルケルセチン、シネンセチンといった天然物由来の物質を有効成分とする排尿障害を改善する組成物が記載されている。 Since the treatment of LUTS may take a long time, it is desired to use an active ingredient that is highly safe for long-term administration. For example, Patent Literature 1 describes a composition for improving urinary disturbance using a substance derived from a natural product such as nobiletin, tangeretin, 3 ′, 4 ′, 5,7-tetramethylquercetin or sinensetin as an active ingredient. .
確かに、特許文献１に記載の組成物の有効成分であるノビレチン、タンゲレチン、３’，４’，５，７−テトラメチルケルセチン及びシネンセチンは、天然物由来のポリメトキシフラボノイドであり、長期間の服用に適している。しかし、本発明者らの調べたところでは、ＬＵＴＳの改善作用は限定的であり、例えば、重度のＬＵＴＳを有する患者にとっては満足できるものではない。 Certainly, nobiletin, tangeretin, 3 ′, 4 ′, 5,7-tetramethylquercetin and sinensetin, which are active ingredients of the composition described in Patent Document 1, are polymethoxyflavonoids derived from natural products, Suitable for taking. However, the present inventors have found that the improvement effect of LUTS is limited and is not satisfactory, for example, for patients with severe LUTS.
そこで、本発明は、特許文献１に記載の組成物と比べて、優れたＬＵＴＳの改善作用を有するＬＵＴＳ改善用組成物を提供することを、本発明が解決しようとする課題とする。 Therefore, an object of the present invention is to provide a LUTS improving composition having an excellent LUTS improving effect as compared with the composition described in Patent Document 1.
本発明者らは、上記課題を解決するために、種々の成分、とりわけ食経験のある成分について鋭意検討を積み重ねたところ、驚くべきことに、ノビレチンやタンゲレチンといったポリメトキシフラボノイドとアミノ酸の一種であるグリシンとを組み合わせることにより、それぞれ単独ではほとんどみられないか、又はみられたとしても程度が小さいＬＵＴＳの改善作用が顕著に大きくなった。このことは、ポリメトキシフラボノイドとグリシンとを組み合わせることによって、相加的というよりもむしろ相乗的ともいえる非常に優れたＬＵＴＳの改善作用が得られることを示す。 The present inventors have conducted intensive studies on various components, particularly those having a dietary experience, in order to solve the above problems, and surprisingly, they are a kind of polymethoxyflavonoids such as nobiletin and tangeretin and amino acids. By combining with glycine, the effect of improving LUTS, which is hardly observed alone or is small even if observed, has been significantly increased. This indicates that the combination of polymethoxyflavonoid and glycine provides a very excellent LUTS improving action that can be said to be synergistic rather than additive.
上記の結果として、本発明者らは、有効成分として、いずれも食経験のあるポリメトキシフラボノイドとグリシンとを組み合わせて含有するＬＵＴＳの改善に有用な組成物を創作することに成功した。本発明は、かかる知見や成功例に基づいて完成された発明である。 As a result of the above, the present inventors succeeded in creating a composition useful for improving LUTS, which contains, as active ingredients, a combination of a polymethoxyflavonoid and glycine, all of which have been eaten. The present invention has been completed based on such knowledge and successful examples.
したがって、本発明の一態様によれば、以下［１］〜［７］の組成物及び方法が提供される。
［１］ポリメトキシフラボノイドと、グリシンとを有効成分として含有する、下部尿路症状改善用組成物。
［２］柑橘類のポリメトキシフラボノイド含有物と、グリシンとを有効成分として含有する、下部尿路症状改善用組成物。
［３］前記ポリメトキシフラボノイドは、ノビレチン、タンゲレチン、３’，４’，５，７−テトラメチルケルセチン及びシネンセチンからなる群から選ばれる少なくとも１種のポリメトキシフラボノイドである、［１］〜［２］のいずれか１項に記載の組成物。
［４］前記組成物は、畜尿症状、排尿症状及び排尿後症状からなる群より選ばれる少なくとも１種の下部尿路症状を改善するための組成物である、［１］〜［３］のいずれか１項に記載の組成物。
［５］前記組成物は、飲食品又は医薬品の形態にある下部尿路症状改善用組成物である、［１］〜［４］のいずれか１項に記載の組成物。
［６］前記組成物は、有効成分の投与量が、下記（１）〜（３）の少なくとも１種の投与量である、［１］〜［５］のいずれか１項に記載の組成物。
（１）成人１日あたりのノビレチンの投与量が３０ｍｇ以上である
（２）成人１日あたりのタンゲレチンの投与量が１５ｍｇ以上である
（３）成人１日あたりのグリシンの投与量が３ｇ以上である
［７］［１］〜［６］のいずれか１項に記載の組成物を、個体に投与することにより、該個体の下部尿路症状を改善する工程を含む、下部尿路症状の改善方法。
Therefore, according to one aspect of the present invention, the following compositions and methods [1] to [7] are provided.
[1] A composition for improving lower urinary tract symptoms, comprising a polymethoxyflavonoid and glycine as active ingredients.
[2] A composition for improving lower urinary tract symptoms, comprising a citrus polymethoxyflavonoid-containing substance and glycine as active ingredients.
[3] The polymethoxyflavonoid is at least one polymethoxyflavonoid selected from the group consisting of nobiletin, tangeretin, 3 ′, 4 ′, 5,7-tetramethylquercetin and sinensetin, [1] to [2]. ] The composition of any one of the above.
[4] The composition according to any one of [1] to [3], wherein the composition is for improving at least one type of lower urinary tract symptom selected from the group consisting of animal urine symptom, urinary symptom, and post-micturition symptom. A composition according to any one of the preceding claims.
[5] The composition according to any one of [1] to [4], wherein the composition is a composition for improving lower urinary tract symptoms in the form of a food or drink or a pharmaceutical product.
[6] The composition according to any one of [1] to [5], wherein the dose of the active ingredient is at least one of the following (1) to (3). .
(1) The dose of nobiletin per adult per day is 30 mg or more. (2) The dose of tangeretin per adult per day is 15 mg or more. (3) The dose of glycine per adult per day is 3 g or more. [7] Improvement of lower urinary tract symptoms, including a step of improving the lower urinary tract symptoms of an individual by administering the composition according to any one of [1] to [6] to the individual. Method.
本発明の一態様の組成物及び方法によれば、天然物由来であり、かつ、食経験がある、ポリメトキシフラボノイド及びグリシンを有効成分として摂取することにより、効果的にＬＵＴＳやＬＵＴＳをもたらす疾患や病態を改善、緩和、回復、治療又は予防することが期待できる。 ADVANTAGE OF THE INVENTION According to the composition and method of one aspect of the present invention, a disease that effectively produces LUTS or LUTS by ingesting a polymethoxyflavonoid and glycine as active ingredients, which are derived from natural products and have a dietary experience. It can be expected to improve, alleviate, remedy, treat or prevent disease and condition.
以下、本発明の一態様である組成物及び方法の詳細について説明するが、本発明の技術的範囲は本項目の事項によってのみに限定されるものではなく、本発明はその目的を達成する限りにおいて種々の態様をとり得る。 Hereinafter, the composition and the method that are one embodiment of the present invention will be described in detail.However, the technical scope of the present invention is not limited only to the items of this item, and the present invention is not limited thereto. May take various aspects.
本明細書における各用語は、別段の定めがない限り、当業者により通常用いられている意味で使用され、不当に限定的な意味を有するものとして解釈されるべきではない。 Unless defined otherwise, the terms herein are used in the sense commonly used by one of ordinary skill in the art and should not be construed as having an unduly restrictive meaning.
「組成物」との用語は、通常用いられている意味のものとして特に限定されないが、例えば、２種以上の物質が組み合わさってなる物であり、具体的には、有効成分と別の物質とが組み合わさってなるもの、有効成分の２種以上が組み合わさってなるものなどが挙げられ、より具体的には、有効成分の１種以上と固形担体又は溶媒の１種以上とが組み合わさってなる固形組成物及び液性組成物などが挙げられる。 The term "composition" is not particularly limited as having a commonly used meaning, and is, for example, a substance obtained by combining two or more kinds of substances. Specifically, the active ingredient and another substance are used. And a combination of two or more active ingredients. More specifically, one or more active ingredients are combined with one or more solid carriers or solvents. Solid compositions and liquid compositions.
「下部尿路症状」との用語は、通常用いられている意味のものとして特に限定されないが、例えば、日本泌尿器科学会編、「男性下部尿路症状・前立腺肥大症診療ガイドライン」（２０１７年４月２０日 発行）の「３ 定義と解説」において定義されているとおりの意味のものである。下部尿路症状には、適当な検査の結果として判明する客観的な症状に加えて、自覚的な主観的な症状が含まれる。 Although the term "lower urinary tract symptoms" is not particularly limited as having a commonly used meaning, for example, Japanese Society of Urology, "Male Lower Urinary Tract Symptoms / Prostatic Hyperplasia Clinical Practice Guidelines" (Apr. 2017) This is the meaning as defined in “3. Lower urinary tract symptoms include subjective symptoms as well as objective symptoms that result from appropriate testing.
本明細書では、下部尿路症状をＬＵＴＳと略す場合がある。ＬＵＴＳには、昼間頻尿、夜間頻尿、尿意切迫感、尿失禁、膀胱知覚といった蓄尿相にみられる症状である畜尿症状；尿勢低下、尿線分割・尿線散乱、尿線途絶、排尿遅延、腹圧排尿、終末滴下といった排尿相にみられる症状である排尿症状；残尿感、排尿後尿滴下といった排尿直後にみられる症状である排尿後症状；膀胱痛症候群、過活動膀胱（ＯＡＢ）、膀胱出口部閉塞といった症状症候群などが含まれる。 In this specification, lower urinary tract symptoms may be abbreviated as LUTS. LUTS include urinary urine symptoms, which are symptoms seen in the urine collection phase such as daytime pollakiuria, nocturia, urgency, urinary incontinence, and bladder perception; hypotension, urinary division / urinary scattering, urinary discontinuation, Urination symptoms, which are symptoms seen in the voiding phase such as urination delay, abdominal pressure voiding, and terminal instillation; post-micturition symptoms, which are symptoms seen immediately after urination such as feeling of residual urine and urinary dripping after urination; bladder pain syndrome, overactive bladder ( OAB) and symptom syndrome such as obstruction of the bladder outlet.
畜尿症状のうち、昼間頻尿は、例えば、日中の排尿回数が多過ぎるという愁訴であるといえる。例えば、１日の排尿回数が８回以上の場合は頻尿と診断され得る。夜間頻尿は、例えば、夜間に排尿のために１回以上起きなければならないという愁訴であるといえる。尿意切迫感は、例えば、急に起こる、抑えられない強い尿意で、我慢することが困難であるという愁訴であるといえる。徐々に強くなる通常の「強い尿意」ではなく、予測困難で「急に起こる強い尿意」の場合に用いられる。尿失禁は、例えば、尿が不随意に漏れるという愁訴であるといえる。尿失禁のうち、夜尿症は、例えば、睡眠中に不随意に尿が漏れるという愁訴であるといえる。尿失禁には、腹圧性尿失禁、切迫性尿失禁、溢流性尿失禁、反射性尿失禁、真性尿失禁などが含まれる。膀胱知覚は、例えば、膀胱充満感はわかるが、明らかな尿意を感じない「低下」や膀胱充満感や尿意がない「欠如」などの５つに分類される。 Among the urine symptoms, daytime pollakiuria can be said to be, for example, a complaint that the number of urinations during the day is too large. For example, if the number of urinations per day is 8 or more, it can be diagnosed as pollakiuria. Nocturia can be a complaint, for example, that it must occur at least once in order to urinate at night. Urgency may be, for example, a complaint that it is difficult to put up with sudden, uncontrollable, strong urgency. It is used in cases where it is difficult to predict and "a sudden strong urination" occurs instead of the usual "strong urination" that gradually increases. Urinary incontinence may be, for example, a complaint that urine leaks involuntarily. Among urinary incontinence, enuresis may be a complaint that urine leaks involuntarily during sleep, for example. Urinary incontinence includes stress incontinence, urge incontinence, overflow incontinence, reflex incontinence, true incontinence and the like. The bladder perception is classified into, for example, five types such as “decrease” in which the user does not feel a clear urination but “clear” in which the user does not feel urinary bladder or bladder fullness or urination.
排尿症状のうち、尿勢低下は、例えば、尿の勢いが弱いという愁訴であるといえる。尿勢低下によって排尿時間が長くなる傾向にある。尿線分割及び尿線散乱は、例えば、尿線が排尿中に分割及び散乱することがあるという愁訴であるといえる。尿線途絶は、例えば、尿線が排尿中に１回以上途切れるという愁訴であるといえる。排尿遅延は、例えば、排尿開始が困難で、排尿準備ができてから排尿開始までに時間がかかるという愁訴であるといえる。腹圧排尿は、例えば、排尿の開始、尿線の維持又は改善のために、腹圧（いきみ）を要するという愁訴であるといえる。終末滴下は、例えば、排尿の終了が延長し尿が滴下する程度まで尿流が低下するという愁訴であるといえる。 Among the urinary symptoms, a decrease in urine intensity can be said to be, for example, a complaint that urinary momentum is weak. Urination time tends to be longer due to lower urine. Urinary segmentation and urinary scatter can be described as complaints that, for example, urine lines can be segmented and scattered during urination. Urinary line interruption can be a complaint, for example, that the urinary line is interrupted one or more times during urination. It can be said that the urination delay is, for example, a complaint that it is difficult to start urination and it takes a long time from the preparation for urination to the start of urination. Abdominal pressure urination may be a complaint that, for example, in order to initiate urination, maintain or improve the urinary line, an abdominal pressure is required. The terminal drip can be considered as a complaint that urinary flow is reduced to such an extent that urination ends and urine drops.
排尿後症状のうち、残尿感は、例えば、排尿後に完全に膀胱が空になっていない感じがするという愁訴であるといえる。残尿感は、実際的な残尿の有無に関係なく生じ得る。排尿後尿滴下は、例えば、排尿直後に不随意的に尿が出てくるという愁訴であるといえる。 Among the symptoms after urination, the feeling of residual urine can be said to be, for example, a complaint that the user feels that the bladder is not completely empty after urination. A feeling of residual urine can occur with or without actual residual urine. It can be said that urinary dripping after urination is, for example, a complaint that urine involuntarily comes out immediately after urination.
ＬＵＴＳの原因となる疾患や病態は限定されず、例えば、畜尿障害や排尿障害を含む下部尿路障害などの下部尿路の疾患及び病態、前立腺の疾患及び病態、神経系の疾患及び病態、薬剤性、多尿、睡眠障害、心因性といったその他の疾患及び病態などが挙げられる。 Diseases and conditions that cause LUTS are not limited, for example, diseases and conditions of the lower urinary tract, such as lower urinary tract disorders including urinary disorders and urinary disorders, diseases and conditions of the prostate, diseases and conditions of the nervous system, Other diseases and conditions such as drug-induced, polyuria, sleep disorders, and psychogenicity are included.
下部尿路の疾患及び病態としては、例えば、膀胱炎、間質性膀胱炎、膀胱癌、膀胱結石、膀胱憩室、週活動膀胱、低活動膀胱などの膀胱の疾患及び病態；尿道炎、尿道狭窄、尿道憩室といった尿道の疾患などが含まれる。前立腺の疾患及び病態としては、例えば、前立腺肥大症、前立腺炎、前立腺癌などが含まれる。神経系の疾患及び病態としては、脳血管障害、認知症、パーキンソン病、多系統萎縮症、正常圧水頭症、進行性核上性麻痩、大脳白質病変などの脳の疾患；脊髄損傷、多発性硬化症、脊髄腫瘍、脊椎変性疾患（脊柱管狭窄症、椎間板ヘルニア）、脊髄血管障害、二分脊椎などの脊髄の疾患；糖尿病、骨盤内手術後などの末梢神経の疾患及び病態などが挙げられる。 Diseases and conditions of the lower urinary tract include, for example, cystitis, interstitial cystitis, bladder cancer, bladder stones, bladder diseases and conditions such as bladder diverticulum, weekly active bladder, and low activity bladder; urethritis, urethral stricture And urethral disorders such as urethral diverticula. Prostate diseases and conditions include, for example, benign prostatic hyperplasia, prostatitis, and prostate cancer. Nervous system diseases and conditions include brain diseases such as cerebrovascular disorder, dementia, Parkinson's disease, multiple system atrophy, normal pressure hydrocephalus, progressive supranuclear palsy, cerebral white matter lesions, spinal cord injury, and multiple occurrences Sclerosis, spinal cord tumors, spinal degenerative diseases (spinal canal stenosis, intervertebral disc herniation), spinal vascular disorders, spinal cord diseases such as spina bifida, and peripheral nerve diseases and conditions such as diabetes and after pelvic surgery. .
「症状改善作用」との用語は、通常用いられている意味のものとして特に限定されないが、例えば、症状が出ている状態を症状が出ていない状態へ向かう作用に加えて、症状が出ている状態を悪化させない作用、症状が出ていない状態を維持する作用、症状が出ていない状態から症状が出ている状態へ向かうことを妨げる作用などが含まれる。具体的には、「症状改善作用」には、症状の発生の防止及び遅延並びに発生の危険性の低下；症状及び状態の好転；症状及び状態の悪化の防止及び遅延；症状をもたらす機能の維持並びに悪化の防止及び遅延などを包含するが、これに限定されない。 The term "symptom ameliorating effect" is not particularly limited as having a commonly used meaning, but, for example, in addition to the effect of going from a symptomatic state to an asymptomatic state, It includes an action that does not worsen the state in which the patient is present, an action that maintains the state in which the symptoms do not appear, and an action that prevents the person from going from the state in which the symptoms do not appear to the state in which the symptoms appear. Specifically, the “symptom-ameliorating effect” includes prevention and delay of the onset of symptoms and reduction of the risk of occurrence; improvement of symptoms and conditions; prevention and delay of deterioration of symptoms and conditions; But also includes, but is not limited to, prevention and delay of deterioration.
「ポリメトキシフラボノイド」は、通常用いられている意味のものとして特に限定されないが、例えば、下記一般式（Ｉ）
Ｒ１は水素又は水酸基であり；Ｒ２〜Ｒ１０はそれぞれ独立して水素、−ＯＨ又は−ＯＣＨ３であり、ただし、Ｒ２〜Ｒ１０のうち３個以上は−ＯＣＨ３である。）
で示される化合物である。
The “polymethoxyflavonoid” is not particularly limited as having a commonly used meaning, and for example, may be represented by the following general formula (I)
R 1 is hydrogen or a hydroxyl group; R 2 to R 10 are each independently hydrogen, —OH or —OCH 3 , provided that at least three of R 2 to R 10 are —OCH 3 . )
It is a compound shown by these.
「グリシン」との用語は、通常用いられている意味のものとして特に限定されないが、例えば、示性式がＨ２ＮＣＨ２ＣＯＯＨであるものとして、アミノ酸の略称として「Ｇｌｙ」や「Ｇ」と表記されるものであるということができる。 The term “glycine” is not particularly limited as it has a commonly used meaning. For example, assuming that the descriptive formula is H 2 NCH 2 COOH, “Gly” or “G” is an abbreviation of an amino acid. It can be said that it is written.
本発明の一態様の組成物は、有効成分として、少なくともポリメトキシフラボノイド及びグリシンを含有する。本発明の一態様の組成物は、これらの有効成分を含有することにより、下部尿路症状改善作用を有する。 The composition of one embodiment of the present invention contains at least polymethoxyflavonoid and glycine as active ingredients. The composition of one embodiment of the present invention has a lower urinary tract symptom improving effect by containing these active ingredients.
本発明の一態様の組成物におけるポリメトキシフラボノイドは特に限定されないが、例えば、一般式（Ｉ）においてＲ３及びＲ４のうち少なくとも１個がメトキシ基であり、かつ、Ｒｙ〜Ｒ１０のうち少なくとも２個がメトキシ基であるポリメトキシフラボノイドなどが挙げられ、好ましくはノビレチン、タンゲレチン、３’，４’，５，７−テトラメチルケルセチン及びシネンセチンである。ポリメトキシフラボノイドは、これらのうちの１種を単独で、又は２種以上を組み合わせて使用できる。 The polymethoxyflavonoid in the composition of one embodiment of the present invention is not particularly limited. For example, in general formula (I), at least one of R 3 and R 4 is a methoxy group, and R y to R 10 Examples thereof include polymethoxyflavonoids in which at least two of them are methoxy groups, and preferred are nobiletin, tangeretin, 3 ′, 4 ′, 5,7-tetramethylquercetin and sinensetin. One of these polymethoxyflavonoids can be used alone or in combination of two or more.
ポリメトキシフラボノイド及びグリシンは、結晶化された純度の高いポリメトキシフラボノイド及びグリシンに加えて、合成、発酵及び／又は天然物から抽出された状態のポリメトキシフラボノイド含有物及びグリシン含有物であってもよい。ポリメトキシフラボノイド及びグリシンを取得する方法は特に限定されない。例えば、市販されているポリメトキシフラボノイド及びグリシンを使用してもよい。 The polymethoxyflavonoid and glycine may be, in addition to crystallized and pure polymethoxyflavonoid and glycine, polymethoxyflavonoid- and glycine-containing substances extracted from synthetic, fermented and / or natural products. Good. The method for obtaining polymethoxyflavonoid and glycine is not particularly limited. For example, commercially available polymethoxyflavonoids and glycine may be used.
一般的に、柑橘類の果皮などには、ポリメトキシフラボノイドが多く含まれていることが知られている。そこで、ポリメトキシフラボノイドは、ポリメトキシフラボノイドを含有する柑橘類の部分や該部分から抽出して得られる抽出物などのポリメトキシフラボノイド含有物であってもよい。すなわち、本発明の別の一態様の組成物は、有効成分として、少なくとも柑橘類のポリメトキシフラボノイド含有物及びグリシンを含有する。 In general, it is known that citrus peels and the like contain a large amount of polymethoxyflavonoids. Thus, the polymethoxyflavonoid may be a polymethoxyflavonoid-containing substance such as a citrus portion containing the polymethoxyflavonoid or an extract obtained by extracting from the portion. That is, the composition of another embodiment of the present invention contains at least citrus polymethoxyflavonoid-containing substances and glycine as active ingredients.
柑橘類は、ノビレチン、タンゲレチン、３’，４’，５，７−テトラメチルケルセチン、シネンセチンといったポリメトキシフラボノイドを含有する柑橘類植物であれば特に限定されない。柑橘類としては、例えば、キノット、ジャッファ・オレンジ、ジョッパ、ネーブルオレンジ、バレンシアオレンジ、福原オレンジ、ブラッドオレンジ、ベルガモットなどのオレンジ類；オランジェロ、グレープフルーツなどのグレープフルーツ類；カボス、清岡橙、コブミカン、三宝柑、シークヮーサー、シトロン、スダチ、ダイダイ、新姫、ブッシュカン、ゆうこう、柚柑、ユズ、ライム、レモンなどの香酸柑橘類；カクテルフルーツ、カワノナツダイダイ、黄蜜柑、ジャバラ、湘南ゴールド、スウィーティー、夏ミカン、八朔（ハッサク）、はるか、媛小春、日向夏などの雑柑類；安芸の輝き（デコポン）、伊予柑、愛媛果試第２８号、清見、佐賀果試３４号（デコポン）、師恩の恵、シラヌヒ（デコポン）、せとか、せとみ、大将季（デコポン）、タンカン、はるみ、肥の豊（デコポン）、マーコット、麗紅などのタンゴール類；アグリフルーツ、サマーフレッシュ、スイートスプリング、セミノール、タンジェロ、ミネオラなどのタンジェロ類；安政柑、河内晩柑、晩白柚、ブンタン（ザボン）などのブンタン類；温州ミカン、大津四号、カラマンシー、甘平、紀州ミカン、コウジ（柑橘類）、桜島ミカン、タチバナ、藤中みかん、ポンカン、マンダリンオレンジなどのミカン類；カラタチなどのカラタチ属；長葉金柑、長実金柑、寧波金柑、福州金柑、香港金柑、丸実金柑などのキンカン属などが挙げられるが、好ましくはミカン科ミカン亜科カンキツ属後生カンキツ亜属ミカン区の柑橘類及びミカン科ミカン亜科カンキツ属初生カンキツ亜族ダイダイ区の柑橘類であり、より好ましくはシークヮーサー（Ｃｉｔｒｕｓ ｄｅｐｒｅｓｓａ）、ウンシュウミカン（Ｃ．ｕｎｓｈｉｕ）、タチバナ（Ｃ．ｔａｃｈｉｂａｎａ）、コウジ（Ｃ．ｌｅｉｏｃａｒｐａ）、ギリミカン（Ｃ．ｔａｒｄｉｖａ）、ジミカン（Ｃ．ｓｕｃｃｏｓａ）、キシュウ（Ｃ．ｋｉｎｏｋｕｎｉ）、コベニミカン（Ｃ．ｅｒｙｔｈｒｏｓａ）、スンキ（Ｃ．ｓｕｎｋｉ）、チチュウカイマンダリン（Ｃ．ｄｅｌｉｃｉｏｓａ）、キング（Ｃ．ｎｏｂｉｌｉｓ）、ポンカン（Ｃ．ｒｅｔｕｃｕｌａｔａ）、ダンシータンジェリン（Ｃ．ｔａｎｇｅｒｉｎａ）、ハナユ（Ｃ．ｈａｎａｙｕ）、マンダリンオレンジ（Ｃ．ｒｅｔｉｃｕｌａｔａ）、サンキ（Ｃ．ｓｕｎｋｉ）、コウライタチバナ（Ｃ．ｎｉｐｐｏｋｏｒｅａｎａ）、シラヌヒ及び清見などであり、さらに好ましくはシークヮーサーである。また、これらの柑橘類は１種又は２種以上であればよく、上記具体例として挙げた柑橘類の交配種であってもよい。 The citrus is not particularly limited as long as it is a citrus plant containing polymethoxyflavonoids such as nobiletin, tangeretin, 3 ′, 4 ′, 5,7-tetramethylquercetin and sinensetin. As the citrus, for example, oranges such as quinotto, Jaffa orange, Joppa, navel orange, Valencia orange, Fukuhara orange, blood orange, bergamot; grapefruits such as orangero, grapefruit; Perfumed citrus fruits such as Shikuwasa, Citron, Sudachi, Daidai, Niihime, Bushkan, Yuko, Yukan, Yuzu, Lime, Lemon; Cocktail fruit, Kawanonut Daidai, Yellow tangerine, Bellows, Shonan Gold, Sweetie, Summer orange, Miscellaneous fruits such as Hassaku, Haruka, Ehime Koharu, and Hyuga Summer; Aki radiance (Dekopon), Iyokan, Ehime Kaseki No. 28, Kiyomi, Saga Kasai 34 (Dekopon), Shion no Megumi, Shiranuhi (Dekopon), Setoka, Setomi, General Tangols such as copon), tankan, harumi, fertilizer (decopon), marcot, liquor; tangero such as agrifruit, summer fresh, sweet spring, seminole, tangero, Mineola; anseikan, Kawachi late citrus, evening Mandarin oranges such as white yuzu and buntan (pomelo); Mandarin oranges such as Unshu mandarin orange, Otsu-shi, Kalamansi, Kanpei, Kishu mandarin orange, Koji (citrus), Sakurajima mandarin orange, Tachibana, Fujinaka mandarin orange, ponkan, mandarin orange; Genus citrus such as citrus; citrus genus such as long-leaf citrus, citrus citrus, ningbo citrus, fuzhou citrus, hongkong citrus, and citrus citrus, but preferably citrus subgenus citrus The citrus of the citrus and the citrus subgenus of the citrus subfamily Daidai citrus More preferably Citrus depressa (Citrus depressa), satsuma mandarin (C.unshiu), Tachibana (C.tachibana), koji (C.leiocarpa), Girimikan (C.tardiva), Jimikan (C.succosa), distichum (C.Kinokuni ), Kobenimikan (C.erythrosa), Sunki (C.sunki), Chichuuka Lee Mandarin (C.deliciosa), King (C.nobilis), ponkan (C.retuculata), Dan Sea Tangerine (C.tangerina), Hanayu (C .hanayu), mandarin orange (C.reticulata), Sanki (C.sunki), Stewartia Tachibana (C. nippocoreana ), shiranuhi and kiyomi , and more preferably a seeker. Further, these citrus fruits may be of one kind or two or more kinds, and may be hybrids of the citrus fruits mentioned as the specific examples.
柑橘類のポリメトキシフラボノイド含有物は、ポリメトキシフラボノイドを含有する部分であれば、果実、根、幹、枝、葉、花のいずれの部分を用いてもよいが、ポリメトキシフラボノイドを多く含有することが知られている果実及び果皮であることが好ましく、乾燥果皮粉末であることがより好ましい。柑橘類のポリメトキシフラボノイド含有物は、例えば、柑橘類の果実から果肉に含まれる果汁を搾り出すようになされる搾汁処理により得られる搾汁残渣であってもよい。 The citrus polymethoxyflavonoid-containing material may be any part of a fruit, a root, a trunk, a branch, a leaf, and a flower, as long as it contains a polymethoxyflavonoid, but contains a large amount of polymethoxyflavonoid. Are preferably fruits and pericarp, and more preferably dried pericarp powder. The citrus polymethoxyflavonoid-containing material may be, for example, a juice residue obtained by a juice treatment for squeezing juice contained in pulp from citrus fruits.
柑橘類のポリメトキシフラボノイド抽出物は、ポリメトキシフラボノイドを高濃度で含有する柑橘類の抽出物であることが好ましい。柑橘類のポリメトキシフラボノイド抽出物におけるポリメトキシフラボノイド濃度（含有量）は特に限定されないが、例えば、柑橘類のポリメトキシフラボノイド抽出物の乾燥質量あたりポリメトキシフラボノイドが１％ｗｔ％以上、好ましくは１０ｗｔ％以上である。それぞれの上限は特に限定されないが、典型的にはポリメトキシフラボノイドの総量として１００ｗｔ％である。柑橘類のポリメトキシフラボノイド抽出物におけるポリメトキシフラボノイドの含有量は、国際公開第２０１４／０５７７２７号明細書に記載の方法によって測定できる。 The citrus polymethoxyflavonoid extract is preferably a citrus extract containing a high concentration of polymethoxyflavonoid. The polymethoxyflavonoid concentration (content) in the citrus polymethoxyflavonoid extract is not particularly limited. For example, the polymethoxyflavonoid is 1% by weight or more, preferably 10% by weight or more per dry mass of the citrus polymethoxyflavonoid extract. It is. The upper limit of each is not particularly limited, but is typically 100 wt% as the total amount of polymethoxyflavonoid. The content of the polymethoxyflavonoid in the citrus polymethoxyflavonoid extract can be measured by the method described in WO 2014/057772.
柑橘類からポリメトキシフラボノイドを抽出する工程は特に限定されないが、例えば、柑橘類の果実や搾汁残渣を、メタノールやエタノールなどのポリメトキシフラボノイド可溶性の有機溶媒で抽出処理する工程などが挙げられる。この際、柑橘類の果実や搾汁残渣を抽出処理に供する前に、乾燥処理、細断処理、粉末化処理、アワモリ菌などを用いた発酵処理に供することや該抽出処理の後にアルカリ処理することにより得た不溶性成分を再度抽出処理に供することなどをすれば、ノビレチン及びタンゲレチンなどのポリメトキシフラボノイドが高含有率又は高含有量で存在する柑橘類のポリメトキシフラボノイド抽出物を得ることができる。このような柑橘類のポリメトキシフラボノイド抽出物を得る方法については、例えば、国際公開第２０１４／０５７７２７号明細書や特開２０１５−２０２０６５号公報などを参照できる。 The step of extracting polymethoxyflavonoids from citrus fruits is not particularly limited, and includes, for example, a step of extracting citrus fruits and juice residue with a polymethoxyflavonoid-soluble organic solvent such as methanol or ethanol. At this time, before subjecting the citrus fruits and squeezed residue to the extraction treatment, drying treatment, shredding treatment, pulverization treatment, fermentation treatment using awamori fungi, etc. or alkali treatment after the extraction treatment By subjecting the insoluble component obtained by the above to an extraction treatment again, a citrus polymethoxyflavonoid extract having a high content or a high content of polymethoxyflavonoids such as nobiletin and tangeretin can be obtained. For a method for obtaining such a citrus polymethoxyflavonoid extract, for example, International Publication WO2014 / 057772, JP-A-2015-202665, and the like can be referred to.
本発明の一態様の組成物が有する下部尿路症状改善作用は、下部尿路症状の少なくともいずれか１種の症状を改善する作用であれば特に限定されないが、例えば、畜尿症状、排尿症状、排尿後症状及び過活動膀胱などが挙げられ、好ましくは頻尿、昼間頻尿、夜間頻尿及び尿意切迫感；尿勢低下及び尿線途絶；残尿感；前立腺肥大並びに過活動膀胱である。 The lower urinary tract symptom-ameliorating effect of the composition of one embodiment of the present invention is not particularly limited as long as it is an effect of improving at least one type of lower urinary tract symptom. , Post-micturition symptoms and overactive bladder, preferably urinary frequency, nocturia, nocturia and urgency; urinary dysfunction and urinary discontinuation; residual urine; prostatic hypertrophy and overactive bladder .
下部尿路症状改善作用は、本発明の一態様の組成物を服用する個体に対して、服用前と一定期間の服用後に、下部尿路症状に関する聴取又は質問票による回答により評価することができる。聴取する際の質問事項としては日中及び夜間の排尿回数、質問票としては過活動膀胱症状スコア（ＯＡＢＳＳ）質問票、国際前立腺症状スコア（ＩＰＳＳ）及びＩＰＳＳ−ＱＯＬスコア質問票を含めることが好ましい。各質問票については、日本泌尿器科学会編、「男性下部尿路症状・前立腺肥大症診療ガイドライン」（２０１７年４月２０日 発行）に記載のものを用いることができる。 The lower urinary tract symptom ameliorating effect can be evaluated for individuals taking the composition of one embodiment of the present invention by listening to or answering a questionnaire regarding lower urinary tract symptoms before and after taking for a certain period of time. . It is preferable to include the number of urinations during the day and night as the question items to be heard, and to include the overactive bladder symptom score (OABSS) questionnaire, the international prostate symptom score (IPSS) and the IPSS-QOL score questionnaire as the questionnaire. . As for each questionnaire, those described in "Guidelines for Treatment of Male Lower Urinary Tract Symptoms / Prostatic Hyperplasia" (published on April 20, 2017) edited by the Japanese Urological Association can be used.
下部尿路症状改善作用は、後述する実施例に記載がある方法により、本発明の一態様の組成物を服用する個体に対して、服用前と一定期間の服用後との間に、統計的に有意な低下がみられるか否かにより評価することができる。例えば、服用から３週間又は６週間後に、服用前に対して「夜間排尿回数」、「ＯＡＢＳＳ夜間回数」、「ＯＢＳＳ切迫感」、「ＩＰＳＳ残尿」、「ＩＰＳＳ頻尿」及び「ＩＰＳＳ尿意切迫」からなる群から選ばれる１種、２種、３種、４種、５種又は６種の項目について統計的に有意な低下がみられる場合に、下部尿路症状改善作用があると評価することができる。本発明の一態様の組成物が有する下部尿路症状改善作用の程度は特に限定されないが、例えば、ポリメトキシフラボノイド単独が有する下部尿路症状改善作用及び／又はグリシン単独が有する下部尿路症状改善作用よりも大きい程度である。 The lower urinary tract symptom ameliorating effect is statistically significant between an individual taking the composition of one embodiment of the present invention and before taking the composition for a certain period of time by the method described in Examples below. Can be evaluated based on whether a significant decrease is observed. For example, 3 weeks or 6 weeks after the administration, “nocturnal urination frequency”, “OABSS night frequency”, “OBSS urgency”, “IPSS residual urine”, “IPSS urinary frequency”, and “IPSS urgency” Is evaluated as having a lower urinary tract symptom-improving effect when one, two, three, four, five, or six of the items selected from the group consisting of: be able to. Although the degree of lower urinary tract symptom improving effect of the composition of one embodiment of the present invention is not particularly limited, for example, lower urinary tract symptom improving effect of polymethoxyflavonoid alone and / or lower urinary tract symptom improvement of glycine alone To a greater extent than the effect.
本発明の一態様の組成物は、下部尿路症状改善作用を有することによって、安眠効果、体力増強効果、尿不安解消効果などの様々な効果を奏することが期待されるものであることから、睡眠促進用組成物、安眠用組成物、体力増強用組成物、尿不安解消用組成物、ＱＯＬ（Ｑｕａｌｉｔｙ ｏｆ ｌｉｆｅ）改善用組成物といった態様をとり得る。 Since the composition of one embodiment of the present invention has a lower urinary tract symptom improving effect, it is expected to exhibit various effects such as a sleep resting effect, a physical strength enhancing effect, and an urinary anxiety relieving effect. Embodiments such as a composition for promoting sleep, a composition for sleeping well, a composition for enhancing physical strength, a composition for relieving urinary anxiety, and a composition for improving QOL (Quality of life) can be taken.
ポリメトキシフラボノイド及びグリシンは、長期にわたりヒトに摂取されてきた実績があり安全性が高いことから、本発明の一態様の組成物は、実用性が高く、そのままで、又は加工することにより、種々の用途に適用可能である。 Since polymethoxyflavonoids and glycine have a long track record of being ingested by humans and are highly safe, the composition of one embodiment of the present invention has high practicability and can be used as it is or by processing. It is applicable to the use of.
本発明の一態様の組成物は、その摂取方法について特に限定されず、例えば、経口的又は非経口的に適用され得る。非経口的な適用としては、皮内、皮下、静脈内、筋肉内投与などによる注射及び注入；経皮；鼻、咽頭などの粘膜からの吸入などが挙げられるが、これらに限定されない。 The composition of one embodiment of the present invention is not particularly limited with respect to the method of ingestion, and may be applied, for example, orally or parenterally. Parenteral applications include, but are not limited to, injection and infusion by intradermal, subcutaneous, intravenous, intramuscular administration, and the like; transdermal; inhalation through mucous membranes such as the nose and pharynx.
本発明の一態様の組成物の摂取個体は特に限定されず、例えば、動物、中でも哺乳類が挙げられ、哺乳類としてはヒト、イヌ、ネコ、ウシ、ウマ、ブタ、ヒツジなどが挙げられ、これらの中でもヒトであることが好ましい。摂取個体は、健常な個体であってもよいが、下部尿路症状の改善が望まれる個体であることが好ましい。 Individuals taking the composition of one embodiment of the present invention are not particularly limited, and include, for example, animals, especially mammals, and the mammals include humans, dogs, cats, cows, horses, pigs, sheep, and the like. Among them, humans are preferred. The ingesting individual may be a healthy individual, but is preferably an individual in which improvement of lower urinary tract symptoms is desired.
本発明の一態様の組成物は、通常用いられる形態であれば特に限定されず、例えば、固形状、液状、ゲル状、懸濁液状、クリーム状、シート状、スティック状、粉状、粒状、顆粒状、錠状、棒状、板状、ブロック状、ペースト状、カプセル状、カプレット状などの各形態を採り得る。 The composition of one embodiment of the present invention is not particularly limited as long as it is a commonly used form.For example, solid, liquid, gel, suspension, cream, sheet, stick, powder, granule, Each form such as granule, tablet, rod, plate, block, paste, capsule, caplet and the like can be adopted.
本発明の一態様の組成物は、下部尿路症状改善作用を有する限り、有効成分と他の成分とを組み合わせて含有し得る。すなわち、本発明の一態様の組成物は、ポリメトキシフラボノイド又は柑橘類のポリメトキシフラボノイド抽出物及びグリシンに加えて、本発明の目的を達成し得る限り、他の成分として種々のものを配合できる。 The composition of one embodiment of the present invention may contain a combination of an active ingredient and another ingredient as long as the composition has a lower urinary tract symptom improving effect. That is, in the composition of one embodiment of the present invention, in addition to the polymethoxyflavonoid or the citrus polymethoxyflavonoid extract and glycine, various other components can be blended as long as the object of the present invention can be achieved.
他の成分としては、例えば、糖質甘味料、安定化剤、乳化剤、澱粉、澱粉加工物、澱粉分解物、食塩、着香料、着色料、酸味料、風味原料、栄養素、果汁、卵などの動植物性食材、賦形剤、増量剤、結合剤、増粘剤、香油、保存剤、緩衝剤、光沢剤などの通常の食品加工や医薬品加工に使用される添加物などを挙げることができる。他の成分の使用量は、本発明の課題の解決を妨げない限り特に限定されず、適宜設定され得る。 Other components include, for example, sugar sweeteners, stabilizers, emulsifiers, starch, processed starch, degraded starch, salt, flavoring agents, coloring agents, sour agents, flavor raw materials, nutrients, fruit juice, eggs, etc. Examples thereof include additives used in normal food processing and pharmaceutical processing, such as animal and plant foods, excipients, extenders, binders, thickeners, balms, preservatives, buffers, and brighteners. The use amount of the other components is not particularly limited as long as it does not prevent the solution of the problem of the present invention, and can be appropriately set.
賦形剤としては、例えば、乳糖、ブドウ糖、白糖、マンニトール、馬鈴薯デンプン、デキストリン、トウモロコシデンプン、炭酸カルシウム、リン酸カルシウム、硫酸カルシウム、結晶セルロース、カンゾウ末、ゲンチアナ末などを挙げることができる。結合剤としては、例えば、デンプン、トラガントゴム、ゼラチン、シロップ、ポリビニルアルコール、ポリビニルエーテル、ポリビニルピロリドン、ヒドロキシプロピルセルロース、メチルセルロース、エチルセルロース、カルボキシルメチルセルロースなどを挙げることができる。崩壊剤としては、例えば、デンプン、寒天、ゼラチン末、カルボキシメチルセルロースナトリウム、カルボキシメチルセルロースカルシウム、結晶セルロース、炭酸カルシウム、メチルセルロース、エチルセルロース、カルボキシルメチルセルロースなどを挙げることができる。滑沢剤としては、例えば、タルク、ステアリン酸マグネシウムなどを挙げることができる。着色剤としては、飲食品や経口用医薬品に添加することが許容されているものなどを使用することができ、特に限定されない。 Examples of the excipient include lactose, glucose, sucrose, mannitol, potato starch, dextrin, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, crystalline cellulose, licorice powder, gentian powder and the like. Examples of the binder include starch, tragacanth gum, gelatin, syrup, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, ethylcellulose, carboxymethylcellulose and the like. Disintegrators include, for example, starch, agar, gelatin powder, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crystalline cellulose, calcium carbonate, methylcellulose, ethylcellulose, carboxymethylcellulose and the like. Examples of the lubricant include talc, magnesium stearate and the like. As the coloring agent, those permitted to be added to foods and drinks and oral drugs can be used and are not particularly limited.
錠剤や顆粒剤とする場合には、所望により、白糖、ゼラチン、精製セラック、グリセリン、ソルビトール、エチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、フタル酸セルロースアセテート、ヒドロキシプロピルメチルセルロースフタレート、メチルメタクリレート、メタアクリル酸重合体などを用いてコーティングしてもよく、複数層でコーティングすることもできる。さらに顆粒剤や粉剤をエチルセルロースやゼラチンのようなカプセルに詰めてカプセル剤とすることもできる。 In the case of tablets and granules, if desired, sucrose, gelatin, purified shellac, glycerin, sorbitol, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropyl methylcellulose phthalate, methyl methacrylate, The coating may be performed using a methacrylic acid polymer or the like, or may be performed using a plurality of layers. In addition, granules and powders can be filled into capsules such as ethyl cellulose or gelatin to form capsules.
本発明の一態様の組成物におけるポリメトキシフラボノイド及び柑橘類のポリメトキシフラボノイド抽出物の含有量は、グリシンと組み合わせることにより下部尿路症状改善作用が認められる量であれば特に限定されないが、経口用組成物としては、例えば、組成物全体に対して、ポリメトキシフラボノイドが０．１ｍｇ〜１０，０００ｍｇ、好ましくは１ｍｇ〜１，０００ｍｇ、より好ましくは１０ｍｇ〜５００ｍｇ、さらに好ましくは２０ｍｇ〜１００ｍｇになるような量であり；ノビレチンが０．０１ｍｇ〜１，０００ｍｇ、好ましくは１ｍｇ〜５００ｍｇ、より好ましくは１０ｍｇ〜２００ｍｇ、さらに好ましくは２０ｍｇ〜１００ｍｇになるような量であり；及び／又は、タンゲレチンが０．０１ｍｇ〜１，０００ｍｇ、好ましくは１ｍｇ〜５００ｍｇ、より好ましくは５ｍｇ〜２００ｍｇ、さらに好ましくは１０ｍｇ〜１００ｍｇになるような量である。 The content of the polymethoxyflavonoid and the citrus polymethoxyflavonoid extract in the composition of one embodiment of the present invention is not particularly limited as long as the lower urinary tract symptom-improving effect is observed in combination with glycine, and As the composition, for example, the polymethoxyflavonoid is 0.1 mg to 10,000 mg, preferably 1 mg to 1,000 mg, more preferably 10 mg to 500 mg, and still more preferably 20 mg to 100 mg, based on the whole composition. Nobiletin in an amount of 0.01 mg to 1,000 mg, preferably 1 mg to 500 mg, more preferably 10 mg to 200 mg, even more preferably 20 mg to 100 mg; and / or tangeretin in an amount of 0.1 mg to 1000 mg. 01 mg to 1,000 mg, preferably 1 mg to 500 mg, more preferably 5Mg～200mg, more preferably in an amount such that 10 mg to 100 mg.
本発明の一態様の組成物におけるグリシンの含有量は、ポリメトキシフラボノイド又は柑橘類のポリメトキシフラボノイド抽出物と組み合わせることにより下部尿路症状改善作用が認められる量であれば特に限定されないが、経口用組成物としては、例えば、組成物全体に対して、１ｍｇ〜１００，０００ｍｇ、好ましくは１０ｍｇ〜１０，０００ｍｇ、より好ましくは１００ｍｇ〜５，０００ｍｇである。 The content of glycine in the composition of one embodiment of the present invention is not particularly limited as long as the lower urinary tract symptom-improving effect is observed by combining with the polymethoxyflavonoid or the citrus polymethoxyflavonoid extract. The composition is, for example, 1 mg to 100,000 mg, preferably 10 mg to 10,000 mg, more preferably 100 mg to 5,000 mg, based on the whole composition.
本発明の一態様の組成物の摂取量は特に限定されず、摂取個体の年齢、体格、症状などの摂取個体の特性；摂取方法；適用部位などに合わせて適宜設定することができる。本発明の一態様の組成物の摂取量は、例えば、一般成人に対して、１ｍｇ〜２０，０００ｍｇ／日であり、好ましくは０．１ｇ〜５ｇ／日である。 The amount of intake of the composition of one embodiment of the present invention is not particularly limited, and can be appropriately set according to characteristics of the individual, such as the age, physique, and symptoms of the individual; The intake of the composition of one embodiment of the present invention is, for example, 1 mg to 20,000 mg / day, preferably 0.1 g to 5 g / day, for a general adult.
本発明の一態様の組成物の摂取回数は特に限定されないが、例えば、１日１〜３回であり、使用個体の下部尿路症状の程度や摂取量に応じて適宜回数を増減することができる。本発明の一態様の組成物の摂取期間は、一定期間、すなわち３日以上、好ましくは１週間以上、より好ましくは３週間以上、さらに好ましくは６週間以上、なおさらに好ましくは６ヶ月以上にわたって継続的に投与する。本発明の一態様の組成物の摂取は、毎日行うことが好ましいが、期間中継続的に摂取する限り、毎日摂取しなくてもよい。 The number of times of ingestion of the composition of one embodiment of the present invention is not particularly limited, and is, for example, 1 to 3 times a day. it can. The ingestion period of the composition of one embodiment of the present invention lasts for a fixed period, that is, for 3 days or more, preferably 1 week or more, more preferably 3 weeks or more, further preferably 6 weeks or more, and still more preferably 6 months or more. Should be administered. It is preferable that the composition of one embodiment of the present invention be taken every day; however, the composition need not be taken every day as long as it is taken continuously during the period.
本発明の一態様の組成物は、該組成物を単独で、又は該組成物を配合する飲食品用組成物や医薬品用組成物などの形態をとり得る。したがって、本発明の具体的な一態様は、有効成分を含有する、又は本発明の一態様の組成物を含有する、飲食品用組成物、医薬品用組成物、医薬部外品用組成物、化粧品用組成物、動物飼料用組成物などである。 The composition of one embodiment of the present invention can take the form of the composition alone, or a composition for a food or drink or a pharmaceutical composition containing the composition. Therefore, a specific embodiment of the present invention contains an active ingredient, or contains the composition of one embodiment of the present invention, a composition for food and drink, a pharmaceutical composition, a quasi-drug composition, Cosmetic compositions, animal feed compositions and the like.
本発明の一態様の組成物が飲食品用組成物である場合は、摂取後に少なくとも下部尿路症状改善作用が発揮し得る限り、あらゆる飲食品の形態をとり得るが、例えば、カプセル剤、錠剤、顆粒剤、ゼリー、ペーストなどの剤状食品；果汁飲料、野菜ジュース、果物野菜ジュース、茶飲料、コーヒー飲料、スポーツドリンク、清涼飲料、健康飲料などの飲料；ヨーグルトやチーズなどの乳製品；スープ、麺、プリン、ジャムなどの加工飲食品；チューインガム、キャンディー、錠菓、グミゼリー、チョコレート、ビスケット、スナックなどの菓子；アイスクリーム、シャーベット、氷菓などの冷菓；せんべいなどの米菓；羊羹その他の大豆を原料とする菓子などに添加して一般的な飲食品の形態とすることができる。 When the composition of one embodiment of the present invention is a composition for food and drink, it can take any form of food and drink as long as at least the lower urinary tract symptom ameliorating effect can be exhibited after ingestion, for example, capsules and tablets Pharmaceutical foods, such as granules, jellies, and pastes; fruit drinks, vegetable juices, fruit and vegetable juices, tea drinks, coffee drinks, sports drinks, soft drinks, health drinks, and other drinks; dairy products such as yogurt and cheese; soups Processed foods and drinks, such as noodles, puddings, jams; chewing gum, candy, tablets, gummy jelly, chocolate, biscuits, snacks, etc .; ice creams, sorbets, frozen desserts, etc .; rice crackers, such as rice crackers; Can be added to a confectionery or the like made from a raw material to form a general food or drink.
飲食品用組成物の具体的な一態様は、例えば、生体に対して一定の機能性を有する飲食品である機能性飲食品である。機能性飲食品は、例えば、特定保健用飲食品、機能性表示飲食品、栄養機能飲食品、保健機能飲食品、特別用途飲食品、栄養補助飲食品、健康補助飲食品、サプリメント、美容飲食品などのいわゆる健康飲食品に加えて、乳児用飲食品、妊産婦用飲食品、高齢者用飲食品などの特定者用飲食品を包含する。さらに機能性飲食品は、コーデックス（ＦＡＯ／ＷＨＯ合同食品規格委員会）の食品規格に基づく健康強調表示（Ｈｅａｌｔｈ ｃｌａｉｍ）が適用される健康飲食品を包含する。 One specific embodiment of the composition for food and drink is, for example, a functional food and drink which is a food and drink having a certain functionality to a living body. Functional foods and drinks include, for example, foods and drinks for specified health use, functionally labeled foods and drinks, nutritional function foods and drinks, health function foods and drinks, special use foods and drinks, nutritional supplements and drinks, health supplements and drinks, supplements, beauty foods and drinks In addition to so-called healthy foods and drinks, foods and drinks for specific persons, such as foods and drinks for infants, foods and drinks for pregnant women, and elderly people. Further, the functional foods and drinks include health foods and drinks to which a health claim based on food standards of the Codex (FAO / WHO Joint Food Standards Committee) is applied.
飲食品用組成物の包装形態は特に限定されず、適用される形態などに応じて適宜選択できるが、例えば、コーティング紙、ＰＥＴやＰＴＰなどのプラスチック、アルミなどの金属、ガラスなどを素材とするパック、瓶、缶、パウチ、１層又は積層（ラミネート）のフィルム袋などが挙げられる。 The packaging form of the composition for food and drink is not particularly limited and can be appropriately selected depending on the form to be applied. For example, the material is made of coated paper, plastic such as PET or PTP, metal such as aluminum, glass or the like. Examples include packs, bottles, cans, pouches, one-layer or laminated film bags, and the like.
本発明の一態様の組成物が医薬品用組成物である場合は、適用後に少なくとも下部尿路症状改善作用が発揮し、それに伴い下部尿路症状をきたす疾患の予防効果又は治療効果が現われる限り、あらゆる医薬品の形態をとり得る。医薬品用組成物は、本発明の目的を達成し得る限り、柑橘類のポリメトキシフラボノイド抽出物以外の下部尿路症状改善を有する他の生理活性物質を配合してもよい。また、本発明の一態様の医薬品用組成物は、他の生理活性物質を有効成分として含有する他の医薬品と併用してもよい。かかる医薬品としては、例えば、抗コリン剤、α１阻害薬、アドレナリン受容体作動薬（ミラベグロン、ＴＡＫ２５９など）、ポリ硫酸ペントサン、塩酸ヒアルロン酸ナトリウム、フラボキサート、セルニチンポーレンエキス、β３受容体刺激薬などが挙げられるが、これらに限定されない。 When the composition of one embodiment of the present invention is a pharmaceutical composition, at least a lower urinary tract symptom ameliorating effect is exerted after application, and as long as a preventive effect or a therapeutic effect for a disease causing lower urinary tract symptoms appears, It can take any pharmaceutical form. The pharmaceutical composition may contain other physiologically active substances having an improvement in lower urinary tract symptoms other than the citrus polymethoxyflavonoid extract as long as the object of the present invention can be achieved. Further, the pharmaceutical composition of one embodiment of the present invention may be used in combination with another pharmaceutical containing another physiologically active substance as an active ingredient. Examples of such drugs include anticholinergics, α1 inhibitors, adrenergic receptor agonists (such as mirabegron and TAK259), pentosan polysulfate, sodium hyaluronate hydrochloride, flavoxate, sernitine pollen extract, and β3 receptor stimulants. But not limited thereto.
医薬品用組成物の剤型は特に限定されないが、例えば、注射剤（筋肉、皮下、皮内）、経口製剤、点鼻製剤などが例示される。医薬品用組成物は、膀胱炎、間質性膀胱炎、膀胱癌、膀胱結石、膀胱憩室、週活動膀胱、低活動膀胱、尿道炎、尿道狭窄、尿道憩室、前立腺肥大症、前立腺炎、前立腺癌、脳血管障害、認知症、パーキンソン病、多系統萎縮症、正常圧水頭症、進行性核上性麻痩、大脳白質病変、脊髄損傷、多発性硬化症、脊髄腫瘍、脊椎変性疾患（脊柱管狭窄症、椎間板ヘルニア）、脊髄血管障害、二分脊椎、糖尿病、骨盤内手術後などの疾患を治療又は予防するための医薬品用組成物という態様をとり得る。 The dosage form of the pharmaceutical composition is not particularly limited, and examples include an injection (muscle, subcutaneous, intradermal), an oral preparation, a nasal preparation and the like. Pharmaceutical compositions include cystitis, interstitial cystitis, bladder cancer, bladder stones, bladder diverticulum, weekly active bladder, hypoactive bladder, urethritis, urethral stricture, urethral diverticulum, benign prostatic hyperplasia, prostatitis, prostate cancer , Cerebrovascular disease, dementia, Parkinson's disease, multiple system atrophy, normobaric hydrocephalus, progressive supranuclear palsy, cerebral white matter lesion, spinal cord injury, multiple sclerosis, spinal cord tumor, spinal degenerative disease (vertebral canal Stenosis, intervertebral disc herniation), spinal vascular disorders, spina bifida, diabetes, post-pelvic surgery, and the like, in the form of a pharmaceutical composition for treatment or prevention.
本発明の一態様の組成物の製造方法は特に限定されず、例えば、ポリメトキシフラボノイド又は柑橘類のポリメトキシフラボノイド抽出物及びグリシンと、任意に他の成分とを混合して、所望の剤形に成形する方法などが挙げられる。 The method for producing the composition of one embodiment of the present invention is not particularly limited.For example, a polymethoxyflavonoid or a citrus polymethoxyflavonoid extract and glycine are optionally mixed with other components to form a desired dosage form. A molding method may be used.
本発明の一態様の組成物の使用方法は特に限定されないが、例えば、本発明の一態様の組成物が経口用組成物である場合は、経口用組成物をそのまま、若しくは水などとともに、又は水などで希釈するなどして、飲食することにより経口摂取することができる。使用個体の好みなどに応じて、本発明の一態様の組成物と他の固体物や液状物とを混ぜて経口摂取してもよい。本発明の一態様の組成物を口腔崩壊剤形とした場合は、水なしで経口摂取することができる。 The method for using the composition of one embodiment of the present invention is not particularly limited.For example, when the composition of one embodiment of the present invention is an oral composition, the oral composition is used as it is or together with water, or It can be taken orally by diluting with water or the like and eating or drinking. The composition of one embodiment of the present invention and another solid substance or liquid substance may be mixed and orally ingested depending on the preference of the individual to be used. When the composition of one embodiment of the present invention is in an orally disintegrating dosage form, it can be taken orally without water.
本発明の一態様の方法は、本発明の一態様の組成物を個体に投与することにより、該個体の下部尿路症状を改善する工程を含む、下部尿路症状の改善方法である。投与方法や個体の下部尿路症状の改善効果の確認方法などは、上記項目を適宜参照できる。また、本発明の一態様の方法は、本発明の課題を解決し得る限り、上記した工程の前段若しくは後段又は工程中に、種々の工程や操作を加入することができる。 The method of one aspect of the present invention is a method for ameliorating lower urinary tract symptoms, comprising the step of administering the composition of one embodiment of the present invention to an individual, thereby improving the lower urinary tract symptoms of the individual. The above items can be referred to as appropriate for the administration method and the method for confirming the effect of improving the lower urinary tract symptoms of the individual. In addition, in the method of one embodiment of the present invention, various steps and operations can be added before or after the above steps or during the steps as long as the object of the present invention can be solved.
以下、本発明を実施例によりさらに詳細に説明するが、本発明はこれら実施例に限定されるものではなく、本発明の課題を解決し得る限り、本発明は種々の態様をとることができる。なお、実施例中の「排尿障害」は従前の広義の排尿障害を意味し、下部尿路症状と同義である。 Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples, and the present invention can take various aspects as long as the object of the present invention can be solved. . It should be noted that “urinary disorder” in the examples means a conventional urinary disorder in a broad sense, and is synonymous with lower urinary tract symptoms.
［例１．ノビレチン、タンゲレチン及びグリシンを含有する組成物による排尿障害改善評価］
（１−１．目的）
排尿障害のある成人ボランティアに対する、ノビレチン及びタンゲレチン含有物並びにグリシンを含有する製剤の排尿障害改善作用について評価した。
[Example 1. Evaluation of Improvement of Urinary Disorder by Composition Containing Nobiletin, Tangeretin and Glycine]
(1-1. Purpose)
The effect of nobiletin and tangeretin-containing preparations and glycine-containing preparations on the improvement of dysuria in adult volunteers with dysuria was evaluated.
特許第５７３５１８４号公報の実施例１の記載を参照して、シークヮーサーの搾り粕から６０ｗｔ％ノビレチン及び３０ｗｔ％タンゲレチンを含有するノビレチン及びタンゲレチン含有物を得た。 With reference to the description in Example 1 of Japanese Patent No. 5735184, nobiletin containing 60 wt% nobiletin and 30 wt% tangeretin and a tangeretin-containing substance were obtained from the squeezed cake of the Shikuwasa.
（１−２．カプセル剤）
賦形剤としてデキストリンを用いて、ノビレチン及びタンゲレチン含有物 ５０ｍｇと、グリシン ３ｇとを含有するカプセル剤を実施例１のカプセル剤とし、ノビレチン及びタンゲレチン含有物 ５０ｍｇのみを含有するカプセル剤を比較例１のカプセル剤とした。
(1-2. Capsule)
Using dextrin as an excipient, a capsule containing 50 mg of nobiletin and tangeretin and 3 g of glycine was used as the capsule of Example 1, and a capsule containing only 50 mg of nobiletin and tangeretin was used as a comparative example 1. Capsules.
頻尿、夜間頻尿、尿意切迫感及び／又は切迫性尿失禁といった排尿障害の症状が２ヵ月以上前からあるが、治療を受けていない未治療の成人ボランティア４２名を対象例とした。 Forty-two untreated adult volunteers who had been suffering from dysuria such as frequent urination, nocturia, urgency and / or urge incontinence for more than 2 months, but had not received any treatment.
（１−３．群分け）
４２例のうち、２５例（男７例、女１８例、年齢４８±１４歳）を実施例１のカプセル剤を経口的に服用する実施例群とし、残りの１７例（男１３例、女４例、年齢６５±１３歳）を比較例１のカプセル剤を経口的に服用する比較例群とした。
(1-3. Grouping)
Of the 42 cases, 25 cases (7 males, 18 females, age 48 ± 14 years) were taken as the group of examples in which the capsule of Example 1 was taken orally, and the remaining 17 cases (13 males, 13 females) (Four cases, age 65 ± 13 years) was taken as a comparative example group in which the capsule of Comparative Example 1 was taken orally.
（１−４．試験方法）
カプセル剤は、１日１回朝、連日的に服用（内服）した。カプセル剤の服用前（０日）、カプセル剤服用３週間後及びカプセル剤服用６週間後に、各対象例について、排尿関連症状としての日中排尿回数（実数）、夜間排尿回数（実数）、過活動膀胱症状スコア（ＯＡＢＳＳ）、国際前立腺症状スコア（ＩＰＳＳ）及びＩＰＳＳ−ＱＯＬスコアを測定した。このうち、ＯＡＢＳＳ、ＩＰＳＳ及びＩＰＳＳ−ＱＯＬについては、日本泌尿器科学会編、「男性下部尿路症状・前立腺肥大症診療ガイドライン」（２０１７年４月２０日 発行）を参照して測定した。
(1-4. Test method)
The capsule was taken (oral) daily in the morning, every day. Before taking the capsule (day 0), 3 weeks after taking the capsule, and 6 weeks after taking the capsule, for each subject, the number of daily urination (real number), the number of night urination (real number), Active bladder symptom score (OABSSS), international prostate symptom score (IPSS) and IPSS-QOL score were measured. Among them, OABSS, IPSS and IPSS-QOL were measured with reference to "Guidelines for the Management of Lower Urinary Tract Symptoms and Prostatic Hyperplasia in Men" (published on April 20, 2017), edited by the Japanese Urological Association.
測定して得られた数値を各群内で平均±標準偏差で表し、カプセル剤の服用前の数値に対するカプセル剤服用３週間後及びカプセル剤服用６週間後の数値を、ｐａｉｒｅｄ ｔ−ｔｅｓｔで検定して、ｐ＜０．０５を「＊」とし、Ｐ＜０．０１を「＊＊」として統計的に有意なものとした。 The numerical value obtained by the measurement is represented by the mean ± standard deviation within each group, and the numerical value 3 weeks after taking the capsule and 6 weeks after taking the capsule with respect to the value before taking the capsule is tested by a paired t-test. Then, p <0.05 was regarded as “*”, and P <0.01 was regarded as “**”, which was statistically significant.
（１−５．評価）
実施例群及び比較例群の結果をそれぞれ図１及び図２に示す。なお、両群ともに、副作用などの有害事象は認められなかった。
(1-5. Evaluation)
The results of the example group and the comparative example group are shown in FIGS. 1 and 2, respectively. No adverse events such as side effects were observed in both groups.
図１及び図２が示すとおり、比較例群において有意差があるものと認められた項目である「昼間排尿回数」、「ＯＡＢＳＳ夜間回数」、「ＯＡＢＳＳ切迫感」、「ＩＰＳＳ−ＱＯＬ」、「ＩＰＳＳ残尿」、「ＩＰＳＳ尿勢低下」、「ＩＰＳＳ夜間頻尿」及び「ＩＰＳＳ−合計」については、実施例群においても有意差がみられた。特に、「昼間排尿回数」、「ＯＡＢＳＳ夜間回数」、「ＯＡＢＳＳ切迫感」、「ＩＰＳＳ残尿」及び「ＩＰＳＳ尿勢低下」の項目については、比較例群に対して、実施例群において顕著な低下がみられた。 As shown in FIG. 1 and FIG. 2, “daytime urination frequency”, “OABSS night frequency”, “OABSS urgency”, “IPSS-QOL”, “IPSS-QOL” Regarding "IPSS residual urine", "IPSS urinary depression", "IPSS nocturia" and "IPSS-total", significant differences were also observed in the example groups. In particular, the items “daytime urination frequency”, “OABSS nighttime frequency”, “OABSS urgency”, “IPSS residual urine” and “IPSS urinary depression” are remarkable in the example group compared to the comparative example group. The decline was observed.
また、驚くべきことに、比較例群では統計的に有意な低下がみられなかった項目である「夜間排尿回数」、「ＯＡＢＳＳ切迫性尿」、「ＩＰＳＳ頻尿」、「ＩＰＳＳ尿線途絶」及び「ＩＰＳＳ尿意切迫」について、実施例群では統計的に有意な低下がみられた。 In addition, surprisingly, in the comparative example group, the items that did not show a statistically significant decrease were “number of nocturnal urination”, “OABSS urgency urine”, “IPSS urinary frequency”, “IPSS urinary discontinuation”. As for "IPSS urgency", a statistically significant decrease was observed in the example group.
以上の結果より、ノビレチン及びタンゲレチンに加えて、グリシンを含有する組成物は、排尿障害の改善、特に昼夜の排尿回数を低減し、さらに頻尿や排尿の切迫感を改善する作用を有することがわかった。 From the above results, in addition to nobiletin and tangeretin, the composition containing glycine improves urination disorders, in particular, reduces the frequency of urination during the day and night, and further has the effect of improving urinary frequency and urgency. all right.
また、参考例群として、排尿障害のある未治療の成人ボランティア５０例に対して、グリシンのみを含有するカプセル剤を服用させた。上記と同様にして、カプセル剤の服用前（０日）及びカプセル剤服用４週間後に、各対象例について、日中排尿回数（実数）及び夜間排尿回数（実数）を測定した。 As a reference example group, a capsule containing only glycine was taken to 50 untreated adult volunteers having dysuria. In the same manner as described above, the number of daytime urination (real number) and the number of nighttime urination (real number) were measured for each subject before taking the capsule (day 0) and 4 weeks after taking the capsule.
参考例群では日中排尿回数（実数）及び夜間排尿回数（実数）の低減効果は見られなかった。 In the reference example group, no reduction effect of the number of daytime urination (real number) and the number of nighttime urination (real number) was observed.
ノビレチン及びタンゲレチン含有物やグリシンの単独では、昼夜の排尿回数を低減するといった排尿障害の改善作用はほとんどみられないか、又はみられたとしても程度が小さかった。このことを勘案すれば、図１によって示される、ノビレチン及びタンゲレチン含有物並びにグリシンを組み合わせて含有する組成物が有する排尿障害の改善作用は、相加的というよりもむしろ相乗的ともいえる格別顕著に優れた作用であることがわかる。 With nobiletin and tangeretin-containing substances or glycine alone, the effect of improving urinary dysfunction, such as reducing the number of day and night urinations, was hardly observed, or even if observed, the effect was small. In view of this, the effect of improving the urinary dysfunction of the composition containing a combination of nobiletin and tangeretin and glycine, as shown in FIG. 1, is significantly more synergistic rather than additive. It turns out that it is an excellent action.
したがって、ノビレチン及びタンゲレチン含有物並びにグリシンを含有する組成物は、排尿障害改善作用を有する組成物として有用であり、さらに過活動膀胱や尿勢減弱といった男性下部尿路症状や前立腺肥大症の治療や予防についても有用であることが示唆される。 Therefore, a composition containing nobiletin and tangeretin and a composition containing glycine are useful as a composition having a dysuria-improving effect, and are used for treating male lower urinary tract symptoms such as overactive bladder and urinary diminution and prostatic hypertrophy. It is suggested that it is also useful for prevention.
本発明の一態様の組成物は、使用個体に対して下部尿路症状を改善させることが可能になる有用な組成物である。 The composition of one embodiment of the present invention is a useful composition that enables a use individual to improve lower urinary tract symptoms.
Claims (6)
（１）成人１日あたりのノビレチンの投与量が３０ｍｇ以上である
（２）成人１日あたりのタンゲレチンの投与量が１５ｍｇ以上である
（３）成人１日あたりのグリシンの投与量が３ｇ以上である
The composition according to any one of claims 1 to 5, wherein a dose of the active ingredient in the composition is at least one of the following doses (1) to (3).
(1) The dose of nobiletin per adult per day is 30 mg or more. (2) The dose of tangeretin per adult per day is 15 mg or more. (3) The dose of glycine per adult per day is 3 g or more. is there
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